Apoptosis induced by synthetic retinoic acid CD437 on human melanoma A375 cells involves RIG-I pathway.
Human malignant melanoma is notoriously resistant to currently available pharmacological modulation. Our aim was to evaluate the anti-tumor effect of a novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carbo-xylic acid (CD437) on melanoma cell line A375. Analysis of cell morphology showed that CD437 promoted marked apoptosis in A375 cells. To explore the mechanisms of CD437-induced apoptosis, an NF-kappaB-luciferase reporter assay was performed, demonstrating that apoptosis induction by CD437 required activation of transcription factor NF-kappaB. Importantly, based on the findings that RIG-I (retinoic acid inducible gene I) can be induced by retinotic acid and can activate NF-kappaB through a CARD-containing adaptor protein VISA, we proposed a hypothesis that RIG-I was involved in the signal pathway of NF-kappaB activation induced by CD437 through the adaptor protein VISA. By specially cleaving VISA with hepatitis C virus (HCV) non-structural (NS)3/4A, the RIG-I pathway was blocked, with subsequent simultaneous inhibition of CD437-induced NF-kappaB activation and cell apoptosis in A375 cells. These results support our hypothesis and suggest that RIG-I may be a useful intermediate biologic marker for retinoid chemoprevention and treatment studies.
Pan
Min
M
Department of Dermatology, Affiliated Hospital of Qingdao University Medical College, 16 Jiangsu Road, 266003, Qingdao, Shandong, People's Republic of China.
Geng
Songmei
S
Xiao
Shengxiang
S
Ren
Jianwen
J
Liu
Yan
Y
Li
Xiaoli
X
Li
Zhengxiao
Z
Peng
Zhenhui
Z
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000276:immunology / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014162:Transfection; D017361:Viral Nonstructural Proteins / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D008156:Luciferases; D016328:NF-kappa B; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D017361:Viral Nonstructural Proteins; C099555:CD 437; C505371:MAVS protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C437968:PLAAT4 protein, human